The present invention relates to novel compounds for inhibiting glycogen synthase kinase-3 (GSK3β) and/or modulators of NMDA channel activities and their use in regulating biological conditions mediated by GSK3β activity and or NMDA channel activity and, more particularly, to the use of such compounds in the treatment of biological conditions such as neurodegenerative diseases, type II diabetes, cancer and affective disorders. The present invention further relates to methods of treating neurodegenerative disorders using GSK3β inhibitors and NMDA modulators.
Synonyms for GSK3β include Tau protein kinase I (TPK I), FA (Factor A) kinase, kinase FA and ATP-citrate lyase kinase (ACLK). GSK3 exists in two isoforms, i.e. GSK3α and GSK3β, and is a proline-directed serine/threonine kinase originally identified as an enzyme that phosphorylates glycogen synthase. However, it has been demonstrated that GSK3β phosphorylates numerous proteins in vitro such as glycogen synthase, phosphatase inhibitor 1-2, the type-II subunit of cAMP-dependent protein kinase, the G-subunit of phosphatase-1, ATP-citrate lyase, acetyl coenzyme A carboxylase, myelin basic protein, a microtubule-associated protein, a neurofilament protein, an N-CAM cell adhesion molecule, nerve growth factor receptor, c-Jun transcription factor, JunD transcription factor, c-Myb transcription factor, c-Myc transcription factor, L-Myc transcription factor, adenomatous polyposis coli tumor suppressor protein, Tau protein and β-catenin.
GSK3β inhibitors may act to increase the survival of neurons subjected to aberrantly high levels of excitation induced by the neurotransmitter glutamate (Nonaka, S., et al., Proc. Natl. Acad. Sci. USA, 95(3):2642-7, 1998). Glutamate-induced neuronal excitotoxicity is also believed to be a major cause of neurodegeneration associated with acute damage, such as in cerebral ischemia, traumatic brain injury and bacterial infection. Furthermore, it is believed that excessive glutamate signaling is a factor in the chronic neuronal damage seen in diseases such as Alzheimer's, Huntington's, Parkinson's, AIDS associated dementia, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) (Thomas, R J., J. Am. Geriatr Soc., 43:1279-89, 1995.
N-methyl-D-aspartate receptors are critical for neuronal plasticity and survival, whereas their excessive activation produces excitotoxicity and may accelerate neurodegeneration. Stimulation of NMDARs in vitro (cultured rat hippocampal or cortical neurons) and in the adult mouse brain in vivo disinhibited GSK3S via protein phosphatase 1(PP1)-mediated dephosphorylation of GSK3β at the serine 9 residue (Szatmari, E., et al, J. Biol. Chem., 280(11):37526-35, 2005). NMDA-triggered GSK3β activation was mediated by NMDAR that contained the NR2B subunit. These data suggest existence of a feedback loop between GSK3β and PP1 that results in amplification of PP1 activation by GSK3β. The excessive activation of NR2B-PP1-GSK3β-PP1 circuitry may contribute to the neurodegeneration induced by excessive NMDA. GSK3R inhibitors might mimic the action of certain hormones and growth factors, such as insulin, which use the  GSK3β pathway.
GSK3β is considered to be an important player in the pathogenesis of Alzheimer's disease. GSK-3 was identified as one of the kinases that phosphorylate Tau, a microtubule-associated protein, which is responsible for the formation of paired helical filaments (PHF), an early characteristic of Alzheimer's disease. Apparently, abnormal Tau hyperphosphorylation is the cause for destabilization of microtubules and PHF formation. Consequently, GSK-3 inhibitors are believed to be potentially useful for treatment of these and other neurodegenerative disorders. Indeed, disregulation of GSK-3 activity has been recently implicated in several CNS disorders and neurodegenerative diseases, including schizophrenia (Beasley, C., et al., Neurosci Lett., 302(20):117-20, 2001; Kozlovsky, N., et al., Eur. Neuropsychopharmacol, 12:13-25, 2002), stroke, and Alzheimer's disease (AD) (Ghat, R. V. and Budd, S. L., Neurosignals, 11:251-61, 2002; Hernandez, F., et al., J. Neurochem., 83:1529-33, 2002; Lucas, J. J., et al., EMBO J, 20:15):27-39, 2001; Mandelkow, E. M., et al., FEBS Lett., 314(21):315-21, 1992).
It thus would be desirable to provide a class of GSK3β inhibitors that would be useful in the treatment of diseases mediated through GSK3β activity such as bipolar disorder (in particular manic depression), diabetes, Alzheimer's disease, leukopenia, FTDP-17 (Fronto-temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, Pick's disease, Niemann Pick's disease type C, Dementia Pugilistica, dementia with tangles only, dementia with tangles and calcification, Down syndrome, myotonic dystrophy, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Parkinsonism-dementia complex of Guam, AIDS related dementia, Postencephalic Parkinsonism, prion diseases with tangles, subacute sclerosing panencephalitis, frontal lobe degeneration (FLD), argyrophilic grains disease, subacute sclerotizing panencephalitis (SSPE) (late complication of viral infections in the central nervous system), inflammatory diseases, cancer, dermatological disorders such as baldness, neuronal damage, schizophrenia, pain, in particular neuropathic pain. GSK3β inhibitors can also be used to inhibit sperm motility and can therefore be used as male contraceptives.
Ions such as glutamate play a key role in processes related to chronic pain and neurotoxicity, primarily by acting through N-methyl-D-aspartate receptors. Thus, inhibition of such action, by employing ion channel antagonists or negative modulators, can be beneficial in the treatment and control of CNS diseases. NMDA receptor activity produces synaptic plasticity in the central nervous system that affects processes for learning and memory, including long-term potentiation and long-term depression (Dingledine R., Crit. Rev. Neurobiol., 4(1):196, 1988). However, prolonged activation of NMDA receptor under pathological conditions (such as cerebral ischemia and traumatic injury) causes neuronal cell death (Rothman S. M. and Olney J. W., Trends Neurosci., 18(2):57 8, 1995). NMDA receptor-mediated excitotoxicity may contribute to the etiology or progression of several neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Since open channel blockers of NMDA receptors were shown, in the late 1980s, to have potential for therapy of ischemic stroke, the receptor has been considered an attractive therapeutic target for the development of neuroprotective agents. Unfortunately, the development of these compounds as neuroprotectants is often limited by their psychiatric side-effects associated with their undesired pharmacodynamic properties such as slow dissociation from the receptor (Muir K. W. and Lees K. R., Stroke, 26(3):503 13, 1995).
Known NMDA antagonists include ketamine, dextromophan, and 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (“CPP”). Although these compounds have been reported (J. D. Kristensen, et al., Pain, 51:249 253 (1992); P. K. Eide, et al., Pain, 61:221 228 (1995); D. J. Knox, et al., Anaesth. Intensive Care 23:620 622 (1995); and M. B. Max, et al., Clin. Neuropharmacol. 18:360 368 (1995)) to produce symptomatic relief in a number of neuropathies including postherpetic neuralgia, central pain from spinal cord injury, and phantom limb pain, widespread use of these compounds is precluded by their undesirable side effects. Such side effects at analgesic doses include psychotomimetic effects such as dizziness, headache, hallucinations, dysphoria, and disturbances of cognitive and motor function. Additionally, more severe hallucinations, sedation, and ataxia are produced at doses only marginally higher than analgesic doses. Thus, it would be desirable to provide novel NMDA modulators that are absent of undesirable side effects or that produce fewer and/or milder side effects.
NMDA receptors are heteromeric assemblies of subunits, of which two major subunit families designated NR1 and NR2 have been cloned. Without being bound by theory, it is generally believed that the various functional NMDA receptors in the mammalian central nervous system (“CNS”) are only formed by combinations of NR1 and NR2 subunits, which respectively express glycine and glutamate recognition sites. The NR2 subunit family is in turn divided into four individual subunit types: NR2A, NR2B, NR2c and NR2D. Ishii, T., et al., J. Biol. Chem., 268:2836-2843 (1993), and Laurie, D. J., et al., Mol. Brain. Res., 51:23-32 (1997) describe how the various resulting combinations produce a variety of NMDA receptors differing in physiological and pharmacological properties such as ion gating properties, magnesium sensitivity, pharmacological profile, as well as in anatomical distribution.